scholarly journals Sources of Multidrug Resistance in Patients With Previous Isoniazid-Resistant Tuberculosis Identified Using Whole Genome Sequencing: A Longitudinal Cohort Study

2020 ◽  
Vol 71 (10) ◽  
pp. e532-e539 ◽  
Author(s):  
Vijay Srinivasan ◽  
Vu T N Ha ◽  
Dao N Vinh ◽  
Phan V K Thai ◽  
Dang T M Ha ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
De Novo ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
Genomic Distance ◽  
First Line ◽  
Pulmonary Tb ◽  
Resistant Tuberculosis ◽  
Mdr Tb

Abstract Background Meta-analysis of patients with isoniazid-resistant tuberculosis (TB) given standard first-line anti-TB treatment indicated an increased risk of multidrug-resistant TB (MDR-TB) emerging (8%), compared to drug-sensitive TB (0.3%). Here we use whole genome sequencing (WGS) to investigate whether treatment of patients with preexisting isoniazid-resistant disease with first-line anti-TB therapy risks selecting for rifampicin resistance, and hence MDR-TB. Methods Patients with isoniazid-resistant pulmonary TB were recruited and followed up for 24 months. Drug susceptibility testing was performed by microscopic observation drug susceptibility assay, mycobacterial growth indicator tube, and by WGS on isolates at first presentation and in the case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine the genomic relatedness between initial and subsequent isolates. De novo emergence of MDR-TB was assumed where the genomic distance was 5 or fewer single-nucleotide polymorphisms (SNPs), whereas reinfection with a different MDR-TB strain was assumed where the distance was 10 or more SNPs. Results Two hundred thirty-nine patients with isoniazid-resistant pulmonary TB were recruited. Fourteen (14/239 [5.9%]) patients were diagnosed with a second episode of TB that was multidrug resistant. Six (6/239 [2.5%]) were identified as having evolved MDR-TB de novo and 6 as having been reinfected with a different strain. In 2 cases, the genomic distance was between 5 and 10 SNPs and therefore indeterminate. Conclusions In isoniazid-resistant TB, de novo emergence and reinfection of MDR-TB strains equally contributed to MDR development. Early diagnosis and optimal treatment of isoniazid-resistant TB are urgently needed to avert the de novo emergence of MDR-TB during treatment.

scholarly journals A joint cross-border investigation of a cluster of multidrug-resistant tuberculosis in Austria, Romania and Germany in 2014 using classic, genotyping and whole genome sequencing methods: lessons learnt

2017 ◽  
Vol 22 (2) ◽  
Author(s):  
Lena Fiebig ◽  
Thomas A Kohl ◽  
Odette Popovici ◽  
Margarita Mühlenfeld ◽  
Alexander Indra ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Universal Access ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
The European Union ◽  
Cross Border ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

Molecular surveillance of multidrug-resistant tuberculosis (MDR-TB) using 24-loci MIRU-VNTR in the European Union suggests the occurrence of international transmission. In early 2014, Austria detected a molecular MDR-TB cluster of five isolates. Links to Romania and Germany prompted the three countries to investigate possible cross-border MDR-TB transmission jointly. We searched genotyping databases, genotyped additional isolates from Romania, used whole genome sequencing (WGS) to infer putative transmission links, and investigated pairwise epidemiological links and patient mobility. Ten isolates from 10 patients shared the same 24-loci MIRU-VNTR pattern. Within this cluster, WGS defined two subgroups of four patients each. The first comprised an MDR-TB patient from Romania who had sought medical care in Austria and two patients from Austria. The second comprised patients, two of them epidemiologically linked, who lived in three different countries but had the same city of provenance in Romania. Our findings strongly suggested that the two cases in Austrian citizens resulted from a newly introduced MDR-TB strain, followed by domestic transmission. For the other cases, transmission probably occurred in the same city of provenance. To prevent further MDR-TB transmission, we need to ensure universal access to early and adequate therapy and collaborate closely in tuberculosis care beyond administrative borders.

scholarly journals Individualized Treatment of Multidrug-resistant Tuberculosis Using Whole-Genome Sequencing and Expanded Drug-Susceptibility Testing

2020 ◽  
Vol 71 (11) ◽  
pp. 2981-2985
Author(s):  
Navisha Dookie ◽  
Nesri Padayatchi ◽  
Richard J Lessells ◽  
Cherise L Naicker ◽  
Sunitha Chotoo ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Susceptibility Testing ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Individualized Treatment ◽  
Whole Genome ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis

Abstract A case of multidrug-resistant tuberculosis is presented. It highlights the role of whole-genome sequencing, expanded phenotypic drug susceptibility testing, and enhanced case management, offering a more complete understanding of drug susceptibility to Mycobacterium tuberculosis. This approach guides an effective individualized treatment strategy that results in rapid sustained culture conversion.

scholarly journals A generalisable approach to drug susceptibility prediction for M. Tuberculosis using machine learning and whole-genome sequencing

2021 ◽  
Author(s):  
◽  
Alexander S Lachapelle
Keyword(s):  
Machine Learning ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Learning System ◽  
World Health ◽  
Whole Genome ◽  
Resistant Tuberculosis ◽  
Mdr Tb ◽  
Health Organization

Rapid and up-to-date drug susceptibility testing is urgently needed to address the threat of multidrug resistant tuberculosis. We developed a composite machine learning system to predict susceptibility from whole-genome sequences for 13 anti-tuberculosis drugs. We trained, validated and externally tested the system, and assessed its performance against a previously validated mutation catalogue, existing molecular assays, and World Health Organization Target Product Profiles. 174,492 phenotypes and 26,328 isolates from 15 countries were studied. The sensitivity of the model was greater than 90% for all drugs except ethionamide, clofazimine and linezolid. Specificity was greater than 95% for all drugs except ethambutol, ethionamide, and bedaquiline, delamanid and clofazimine. The machine learning system was more sensitive than the catalogue and assay (all p<0.01), and correctly predicted a pan-susceptible regimen with 98% accuracy in MDR-TB samples. The proposed system can help guide therapy and be updated automatically as new resistance emerges.

scholarly journals Transmission of multidrug-resistant tuberculosis in Shimen community in Shanghai, China: a molecular epidemiology study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Zhiying Han ◽  
Jing Li ◽  
Guomei Sun ◽  
Kaikan Gu ◽  
Yangyi Zhang ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
Epidemiological Investigation ◽  
Transmission Pattern ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Recent Transmission ◽  
Mdr Tb

Abstract Background Multidrug-resistant tuberculosis (MDR-TB) has become a major public health problem in China, with mounting evidence suggesting that recent transmission accounts for the majority of MDR-TB. Here we aimed to reveal the transmission pattern of an MDR-TB outbreak in the Jing'an District of Shanghai between 2010 and 2015. Methods We used whole-genome sequencing (WGS) to conduct genomic clustering analysis along with field epidemiological investigation to determine the transmission pattern and drug resistance profile of a cluster with ten MDR-TB patients in combining field epidemiological investigation. Results The ten MDR-TB patients with genotypically clustered Beijing lineage strains lived in a densely populated, old alley with direct or indirect contact history. The analysis of genomic data showed that the genetic distances of the ten strains (excluding drug-resistant mutations) were 0–20 single nucleotide polymorphisms (SNPs), with an average distance of 9 SNPs, suggesting that the ten MDR-TB patients were infected and developed the onset of illness by the recent transmission of M. tuberculosis. The genetic analysis confirmed definite epidemiological links between the clustered cases. Conclusions The integration of the genotyping tool in routine tuberculosis surveillance can play a substantial role in the detection of MDR-TB transmission events. The leverage of genomic analysis in combination with the epidemiological investigation could further elucidate transmission patterns. Whole-genome sequencing could be integrated into intensive case-finding strategies to identify missed cases of MDR-TB and strengthen efforts to interrupt transmission.

Prevalence of Multi-Drug Resistant Tuberculosis among Tuberculosis Patients Attending Chest Clinics in Osun-State, Nigeria

2020 ◽  
Vol 21 (10) ◽  
pp. 939-947
Author(s):  
Gbadebo J. Oyedeji ◽  
Charles Adeyemo ◽  
Affolabi Dissou ◽  
Tope Abiodun ◽  
Oyebode A.T. Alli ◽  
...  
Keyword(s):  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Tuberculosis Control ◽  
First Line ◽  
Tuberculosis Patients ◽  
Resistant Tuberculosis ◽  
Mdr Tb ◽  
Previously Treated ◽  
The Impact

Background: The development of multidrug-resistant tuberculosis (MDR-TB) poses a considerable threat to tuberculosis control programmes in Nigeria. There is an increase in the prevalence of MDR-TB worldwide both among new tuberculosis cases as well as previously-treated ones. There is also a rise in transmission of resistant strains due to an increase in MDR-TB patients largely due to the poor drug compliance and the impact of Human immunodeficiency virus infection. Therefore, we intend to determine the extent of MDR-TB among attendees of chest clinics in Osun-State, Nigeria. Objectives: The objective of this study was to determine the prevalence of MDR-TB among confirmed tuberculosis patients attending chest clinics in Osun-State, Nigeria. Methods: This study was conducted among 207 attendees of chest clinics in Osun-State between June, 2015 and October 15, 2016. Sputum and blood samples of the participants were collected. GeneXpert test was carried out first on the samples for simultaneous identification of MTB and rifampicin resistance. Sputum samples were cultured on Lowenstein-Jensen (L-J) medium using N-acetyl-Lcysteine- sodium hydroxide (NALC-NaOH) decontamination method. Drug susceptibility testing (DST) to three first-line drugs was carried out using the proportion DST method. Results: The prevalence of MTB was found to be 27.5% while the prevalence of MDR-TB from the fifty-seven isolates was 10.5%. Previously treated and new cases had a prevalence of 7.0% and 3.5% MDR-TB, respectively. Seventy (33.8%) participants were positive for HIV infection, out of which twenty-six (12.6%) had co-infection of tuberculosis and HIV. The mono-resistance rates of the three first-line drugs used were: 5.3% and 8.7% for ethambutol (EMB) and isoniazid (INH), respectively. No isolate had mono-resistance (0%) to rifampicin (RIF). Conclusion: This study observed the prevalence of 27.5% MTB and a prevalence of 10.5% MDR-TB among the MTB isolates. The prevalence of TB is high in Osun State. MDR-TB prevalence is higher compared with the national estimate of MDR-TB (5.1%) of 2017. Resistant TB is a threat to national tuberculosis control and it is recommended that all the facilities be equipped to cater to its diagnosis.

scholarly journals Genetic Variation Putatively Associated with Mycobacterium tuberculosis Resistance to Perchlozone, a New Thiosemicarbazone: Clues from Whole Genome Sequencing and Implications for Treatment of Multidrug-Resistant Tuberculosis

Antibiotics ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 669
Author(s):  
Igor Mokrousov ◽  
Anna Vyazovaya ◽  
Gulnora Akhmedova ◽  
Natalia Solovieva ◽  
Eugeni Turkin ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Genetic Variation ◽  
Whole Genome Sequencing ◽  
Treatment Regimen ◽  
Genome Sequencing ◽  
Multidrug Resistant ◽  
Whole Genome ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

Perchlozone ([PCZ] 4-thioureido-iminomethylpyridinium perchlorate) is a new thiosemicarbazone approved for the treatment of multidrug-resistant tuberculosis (MDR-TB) in Russia and some other countries. The ethA and hadABC mutations may confer PCZ resistance. At the same time, ethA mutations are known to mediate resistance to ethionamide (ETH) and prothionamide (PTH). We aimed to study the genetic variation underlying Mycobacterium tuberculosis resistance to PCZ through whole genome sequencing (WGS) of consecutive isolates recovered during long-term treatment. This prospective study included patients admitted in 2018–2019 to the regional tuberculosis dispensary, Kaliningrad, Russia, whose treatment regimen included PCZ. Multiple M. tuberculosis isolates were recovered during PCZ treatment, and the bacterial DNA was subjected to WGS followed by bioinformatics analysis. We identified mutations in the genes putatively associated with PCZ resistance, ethA, and hadA. The most frequent one was a frameshift ethA 106 GA > G (seven of nine patients) and most of the other mutations were also likely present before PCZ treatment. In one patient, a frameshift mutation ethA 702 CT > C emerged after six months of PCZ treatment. A frequent presence of cross-resistance mutations to PCZ and ETH/PTH should be taken into consideration when PCZ is included in the treatment regimen of MDR-TB patients.

scholarly journals KAMI-PMO TB (EDUKASI DAN PENDAMPINGAN PENGAWAS MENELAN OBAT TB) DALAM PENGENDALIAN MDR TB

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Mareta Dea Rosaline ◽  
Santi Herlina
Keyword(s):  
Multidrug Resistant ◽  
T Test ◽  
P Value ◽  
Test Analysis ◽  
Pulmonary Tb ◽  
Drug Ingestion ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb ◽  
Paired T Test

Tuberculosis control in Indonesia is still not optimal. The problem of MDR TB (Multidrug-Resistant Tuberculosis) is an obstacle to controlling TB in Indonesia. MDR TB is caused by no response from TB germs to treatment isoniazid and rifampicin, anti-tuberculosis drugs. TB incidence rate in Serang district ranks second in Banten Province after Tangerang. The number of pulmonary TB cases is due to the lack of public knowledge and awareness about pulmonary TB disease. To reduce the adverse effects of MDR TB requires the involvement of cadres or family members who controlling drug ingestion (PMO). The form of activities carried out through the formation of cadres to care for TB through the KAMI-PMO TB (Education and Assistance for TB Medication Supervisors) in Desa Baros, Kabupaten Serang. The purpose is to increase the commitment, ability, and knowledge of cadres as coordinator of PMO (Drug Swallow Supervisor) to control MDR TB. The method of implementing activities is counseling, demonstrations, and assistance to cadres. The media used were PPT, WE-PMO TB Booklet, and educational videos. The result of the training was an increase in the ability of cadres in providing PMO counseling by 87%. The Paired T-Test analysis results showed a p-value of 0.000, which means that the training conducted affected cadres' knowledge of PMO TB. In conclusion, education and assistance to cadres have a good influence in increasing knowledge and abilities. The expected result is TB care cadres can provide aid and become the coordinator of TB PMO (Drug Ingestion Supervisor).  ABSTRAK:Pengendalian Tuberculosi di Indonesia masih belum optimal.Permasalahan MDR TB (Multidrug Resistant Tuberculosis) merupakan hambatan pengendalian TB di Indonesia. MDR TB disebabkan tidak ada respon kuman TB terhadap pengobatan isoniazid dan rifampizin yang merupakan obat anti tuberculosis. Angka kejadian TB di kabupaten Serang menempati urutan kedua di Provinsi Banten setelah Tangerang, dan banyaknya kasus TB Paru dikarenakan pengetahuan dan kesadaran masyarakat tentang penyakit TB Paru masih kurang. Untuk mengurangi dampak buruk MDR TB dibutuhkan keterlibatan peran serta kader peduli TB atau anggota keluarga yang berperan dalam pengawasan menelan obat (PMO). Bentuk kegiatan yang dilakukan sebagai bentuk pemberdayaan masyarakat melalui pembentukan kader peduli TB  melalui KAMI-PMO TB (Edukasi dan Pendampinga Pengawas Menelan Obat TB) di Desa Baros Kabupaten Serang. Tujuan dari pengabdian masyarakat adalah meningkatkan komitmen, kemampuan dan pengetahuan kader sebagai koordinator PMO (Pengawas Menelan Obat) dalam upaya pengendalian MDR TB. Metode pelaksanaan kegiatan adalah penyuluhan, demontrasi, dan pendampingan kader. Media yang digunakan yaitu PPT, Booklet KAMI-PMO TB , dan video edukasi. Hasil dari kegiatan adalah meningkatnya kemampuan kader dalam memberikan penyuluhan PMO cukup tinggi sebesar 87%. Hasil analisis uji Paired T- Test didapatkan nilai p value 0,000 yang artinya ada pengaruh pelatihan yang dilakukan terhadap pengetahuan kader tentang PMO TB. Kesimpulannya edukasi dan pendampingan kepada kader memiliki pengaruh yang baik  dalam meningkatkan pengetahuan dan kemampuan, sehingga hasil yang diharapkan kader peduli TB dapat melakukan pendampingan pada pasien TB dan menjadi koordinator PMO (Pengawas Menelan Obat) TB dalam upaya pengendalian MDR TB

A Rapid and Accurate Detection Approach for Multidrug-Resistant Tuberculosis Based on PCR-ELISA Microplate Hybridization Assay

2020 ◽  
Vol 51 (6) ◽  
pp. 606-613
Author(s):  
Ye-Cheng Zhou ◽  
Shu-Mei He ◽  
Zi-Lu Wen ◽  
Jun-Wei Zhao ◽  
Yan-Zheng Song ◽  
...  
Keyword(s):  
Clinical Care ◽  
Pcr Amplification ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Hybridization Assay ◽  
Enzyme Linked Immunosorbent Assay ◽  
Resistant Tuberculosis ◽  
Multidrug Resistant Tuberculosis ◽  
Mdr Tb

Abstract Rapid and accurate diagnosis of multidrug-resistant tuberculosis (MDR-TB) is important for timely and appropriate therapy. In this study, a rapid and easy-to-perform molecular test that integrated polymerase chain reaction (PCR) amplification and a specific 96-well microplate hybridization assay, called PCR-ELISA (enzyme-linked immunosorbent assay), were developed for detection of mutations in rpoB, katG, and inhA genes responsible for rifampin (RIF) and isoniazid (INH) resistance and prediction of drug susceptibility in Mycobacterium tuberculosis clinical isolates. We evaluated the utility of this method by using 32 multidrug-resistent (MDR) isolates and 22 susceptible isolates; subsequently, we compared the results with data obtained by conventional drug susceptibility testing and DNA sequencing. The sensitivity and specificity of the PCR-ELISA test were 93.7% and 100% for detecting RIF resistance, and 87.5% and 100% for detecting INH resistance, respectively. These results were comparable to those yielded by commercially available molecular tests such as the GenoType MTBDRplus assay. Based on the aforementioned results, we conclude that the PCR-ELISA microplate hybridization assay is a rapid, inexpensive, convenient, and reliable test that will be useful for rapid diagnosis of MDR-TB, for improved clinical care.

Multidrug-resistant tuberculosis in the Kharkiv Region, Ukraine

2020 ◽  
Vol 24 (5) ◽  
pp. 485-491
Author(s):  
D. Butov ◽  
C. Lange ◽  
J. Heyckendorf ◽  
I. Kalmykova ◽  
T. Butova ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Drug Susceptibility ◽  
Multidrug Resistant ◽  
Drug Susceptibility Testing ◽  
Tb Treatment ◽  
Resistant Tuberculosis ◽  
Poor Treatment ◽  
Mdr Tb ◽  
Observational Cohort

OBJECTIVE: To document the level of drug resistance in MDR-TB patients and to characterize management capacities for their medical care and MDR-TB treatment outcomes in the Kharkiv region of Ukraine. This area has one of the highest frequencies of MDR-TB worldwide.METHODS: A retrospective observational cohort study was performed on registry data from the regional anti-TB dispensary in Kharkiv. All microbiologically confirmed MDR-TB patients registered in 2014 were included. Diagnostic, treatment and post-treatment follow-up data were analysed.RESULTS: Of 169 patients with MDR-TB, 55.0% had pre-extensively drug-resistant (pre-XDR) or XDR resistant patterns. Rapid molecular diagnosis by GeneXpert and liquid M. tuberculosis cultures were only available for 66.9% and 56.8% of patients, respectively. Phenotypic drug-susceptibility testing (DST) for high priority TB drugs (bedaquiline, linezolid, clofazimine) were not available. DST for later generation fluroquinolones was available only in 53.2% of patients. 50.9% of patients had less than 4 drugs in the treatment regimen proven to be effective by DST. More than 23.1% of patients with MDR-TB failed their treatment and only 45.0% achieved a cure.CONCLUSION: The high prevalence of MDR-TB and poor MDR-TB treatment outcomes in the Kharkiv region, is associated with substantial shortages in rapid molecular and phenotypic DST, a lack of high priority MDR-TB drugs, poor treatment monitoring and follow-up capacities.

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